DESCRIPTION: Bioactive, biostable grafts have the potential to replace diseased small-caliber vessels without the complications associated with autologous or current synthetic grafts. A major roadblock in 'off-the-shelf' vascular graft development is the potential for graft re- occlusion due to intimal hyperplasia (IH). A strong empirical correlation exists between graft compliance and long term patency. As such, compliance has been identified as a key determinant of 'off the shelf' graft success. Despite this strong empirical correlation, there has not been a definitive study to demonstrate that a synthetic graft with improved compliance matching does indeed perform similar to an autograft. In addition, the mechanisms by which compliance mismatch would lead to IH are relatively poorly understood. So, the question remains - is compliance matching enough, and if so, why? In the proposed studies, we will first evaluate porcine carotid arteries containing sutured grafts of various compliance values in an established ex vivo organ culture model of IH. These ex vivo studies will aid in the identification of early EC, macrophage and SMC markers associated with alterations in graft compliance. We will then then confirm that similar alterations in cell phenotype are correlated with degree of IH formation in vivo using a porcine model. Upon completion, the proposed studies will: 1) validate a short term organ culture model of IH for screening vascular grafts; 2) provide data linking graft compliance and the early cell phenotypic changes that lead to IH; 3) evaluate the degree to which improved compliance-matching reduces graft re-occlusion by limiting IH. Overall, these results will enable improved design of small-caliber vascular prostheses and will validate a rapid ex vivo screening tool for assessing graft resistance to IH. Future studies will utilize this model to probe the underlying mechanisms that drive graft-induced IH.